Exploring the Potential Application of Glucuronides As a Prognostic Biomarker for Disease

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Faculty of Science and Technology Department of Life and Environmental Science

Exploring the potential application of glucuronides as a prognostic biomarker for disease

Volume 2: References and Appendices

A thesis submitted as part for the requirement of Masters by Research

Jack Wieland

30th September 2019

Contents

References...... 2

Appendices ...... 189

Appendix1: Log Book Evidence for Chapter 7 ...... 190

Appendix 2: Inclusion and exclusion of retrieved articles ...... 200 Colorectal cancer inclusion and exclusion ...... 200 Type 2 Diabetes inclusion and exclusion ...... 222 Parkinson’s disease inclusion and exclusion ...... 230 Prostate cancer inclusion and exclusion ...... 233 Breast cancer inclusion and exclusion ...... 248 Liver cancer inclusion and exclusion ...... 261

Appendix 3: Evidence of permission granted ...... 275

Appendix 4: Supplementary information ...... 277 A4 1.0: Organic anion transporters ...... 277

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Appendices

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Appendix1: Log Book Evidence for Chapter 7

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Appendix 2: Inclusion and exclusion of retrieved articles

Colorectal cancer inclusion and exclusion Genetics Part 1: Title screening Inclusion Scopus 1. Labriet, A., De Mattia, E., Cecchin, E., et al., 2017. Improved progression- free survival in irinotecan-treated metastatic colorectal cancer patients carrying the HNF1A coding variant p.I27L. Frontiers in Pharmacology [online], 8 (712), doi: 10.3389/fphar.2017.00712. 2. Mbatchi, L. C., Robert, J., Ychou, M., et al., 2016. Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients. Clinical Pharmacokinetics [online], 55 (9),1145 - 1157. 3. Hou, H-X., Qu, Y-L., Tang, X-S., et al., 2015.Association of UGT1A1 polymorphisms with irinotecan induced toxicities in advanced colorectal cancer: a Meta-analysis in Asians. Chinese Journal of Cancer Prevention and Treatment [online], 22 (20), 1634 - 1640. 4. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194. 5. Suenaga, M., Fuse, N., Yamaguchi, T., Yamanaka, Y., et al., 2014. Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Journal of Clinical Pharmacology [online], 54 (5), 495 – 502. 6. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one-point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1

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genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 - 402. 7. Park, S. R., Hong, Y. S., Lim, H-S., et al., 2013. Phase i clinical and pharmacokinetic/pharmacogenetic study of a triplet regimen of S- 1/irinotecan/oxaliplatin in patients with metastatic colorectal or gastric cancer. Cancer Chemotherapy and Pharmacology [online], 72 (5), 953 – 964. 8. Xu, J-M., Wang, Y., Ge, F-J., et al., 2013. Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World Journal of Gastroenterology [online], 19 (24), 3899 – 3903. 9. Kim, K-P., Kim, H-S., Sym, S. J., et al., 2013. A UGT1A1*28 and*6 genotype-directed phase i dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology [online], 71 (6), 1609 – 1617. 10. Wang, Y., Shen, L., Xu, N., et al., 2012. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World Journal of Gastroenterology [online], 18 (45), 6635 - 6644. 11. Evrard, A and Mbatchi, L., 2012. Genetic polymorphisms of drug metabolizing enzymes and transporters: The long way from bench to bedside. Current Topics in Medicinal Chemistry [online], 12 (15), 1720 – 1729. 12. Solier, S., Zhang, Y-W., Ballestrero, A., et al., 2012., DNA damage response pathways and cell cycle checkpoints in colorectal cancer: Current concepts and future perspectives for targeted treatment. Current Cancer Drug Targets [online], 12 (4), 356 - 371. 13. Akiyama, Y., Fujita, K-I., Ishida, H., et al., 2012. Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer. Drug Metabolism and Pharmacokinetics [online], 27 (3), 325 – 335. 14. Deenen, M. J., Cats, A., Beijnen, J. H., et al., 2013. Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist [online], 16 (7), 992 - 1005.

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15. Li, J and Bluth, M. H., 2011. Pharmacogenomics of drug metabolizing enzymes and transporters: Implications for cancer therapy. Pharmacogenomics and Personalized Medicine [online], 4 (1), 11 – 33. 16. Wu, B., Kulkarni, K., Basu, S., et al., 2011. First-pass metabolism via UDP- glucuronosyltransferase: A barrier to oral bioavailability of phenolics. Journal of Pharmaceutical Sciences [online], 100 (9), 3655 - 3681. 17. Ramrez, J., Ratain, M. J and Innocenti, F., 2010. Uridine 5́-diphospho- glucuronosyltransferase genetic polymorphisms and response to cancer chemotherapy. Future Oncology [online], 6 (4), 563 – 585. 18. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1 * 28 polymorphism. Cancer Science [online], 101 (3), 722 – 727. 19. Walko, C. M and McLeod, H., 2009. Pharmacogenomic progress in individualized dosing of key drugs for cancer patients. Nature Reviews Clinical Oncology [online], 6 (3), 153 – 162. 20. Wang, M., Sun, D. F., Qing, Y., et al., 2013. Polymorphic expression of UDP-glucuronosyltransferase UGTlA gene in human colorectal cancer. PLoS ONE [online], 8 (2), e57045.

NCBI 1. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2016. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 - 69. 2. Falkowski, S., Woillard, J. B., Postil, D., et al., 2017. Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study. BMC Cancer [online], 17 (1), doi: 10.1186/s12885-017-3728-0. 3. Boyer, J. C., Etienne-Grimaldi, M. C., Thomas, F., et al., 2014. Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan. Bulletin du Cancer [online], 101 (6), 533 – 553. 4. Hung, S. H., Chao, Y., Wu, Y. Y., et al., 2011. Concurrence of UGT1A polymorphism and end-stage renal disease leads to severe toxicities of

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irinotecan in a patient with metastatic colon cancer. Tumori [online], 97 (2), 243 – 247. 5. Inoue, K., Sonobe, M., Kawamura, Y., et al., 2013. Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. The Tohoku Journal of Experimental Medicine [online], 229 (2), 107 – 114. 6. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one-point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 – 402. 7. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 722 – 727.

Web of Science 1. Liu, Y., Ramírez, J., House, L., et al., 2010. The UGT1A1*28 polymorphism correlates with erlotinib's effect on SN-38 glucuronidation. European Journal of Cancer [online], 46 (11), 2097 – 2103. 2. Hirose, K., Kozu, C., Yamashita, K., et al., 2012. Correlation between plasma concentration ratios of SN-38 glucuronide and sn-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene. Oncology Letters [online], 3 (3), 694 – 698. 3. Inoue, K., Sonobe, M., Kawamura, Y., et al., 2013. Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events inCancer Patients Receiving Irinotecan-Based Chemotherapy. Tohoku Journal of Experimental Medicine [online], 229 (2), 107 - 114. 4. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194.

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Google Scholar 1. Cai, X., Tian, C., Wang, L., et al., 2017. Correlative analysis of plasma SN-38 levels and DPD activity with outcomes of FOLFIRI regimen for metastatic colorectal cancer with UGT1A1 *28 and *6 wild type and its implication for individualized chemotherapy. Cancer Biology & Therapy [online], 18 (3),186 – 193. 2. Snozek, C. L., O'Kane, D. J and Algeciras-Schimnich, A., 2009. Pharmacogenetics of solid tumors: directed therapy in breast, lung, and colorectal cancer: a paper from the 2008 william beaumont hospital symposium on molecular pathology. The Journal of Molecular Diagnostics [online], 11 (5), 381 – 389. 3. Onoue, M., Terada, T., Kobayashi, M., et al., 2009. UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients. International Journal of Clinical Oncology [online], 14 (2), 136 – 142. 4. Takano, M., Kato, M., Yoshikawa, T., Sasaki, N., Hirata, J., Furuya, K., Takahashi, M., Yokota, H., Kino, N., Horie, K., Goto, T., Fujiwara, K., Ishii, K., Kikuchi, Y and Kita, T., 2009. Clinical significance of UDP- glucuronosyltransferase 1A1*6 for toxicities of combination chemotherapy with irinotecan and cisplatin in gynecologic cancers: a prospective multi-institutional study. Oncology [online], 76 (5), 315 – 321. 5. Fukui, T., Mitsufuji, H., Kubota, M., et al., 2011. Prevalence of topoisomerase I genetic mutations and UGT1A1 polymorphisms associated with irinotecan in individuals of Asian descent. Oncology Letters [online], 2 (5), 923 – 928. 6. Liu, X and Xu, W., 2014. UGT1A1*28 polymorphisms: a potential pharmacological biomarker of irinotecan-based chemotherapies in colorectal cancer. Pharmacogenomics [online], 15 (9), 1171 – 1174. 7. Li, M., Wang, Z., Guo, J., et al., 2014. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets and Therapy [online], 23 (7), 1653 – 1661.

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8. Wang, J., Joshi, A. D., Corral, R., et al., 2012. Carcinogen metabolism genes, red meat and poultry intake, and colorectal cancer risk. International Journal of Cancer [online], 130 (8), 1898 – 1907. 9. Angstadt, A. Y., Hartman, T. J., Lesko, S. M., et al., 2014.The Effect of UGT1A and UGT2B Polymorphisms on Colorectal Cancer Risk: Haplotype Associations and Gene-Environment Interactions. Genes, Chromosomes & Cancer [online], 53 (6), 454 - 466. 10. Zhang, X., Yin, J. F., Zhang, J., et al., 2017. UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis. Cancer Chemotherapy and Pharmacology [online], 80 (1), 135 – 149. 11. El Bastawisy, A., El-Zeiny, A., Farid, S. F., et al., 2014.UGT1A1*28 Polymorphism in Advanced Colorectal Cancer: The Story Is Not Yet Ended. Journal of Clinical Oncology [online], 32 (3), 53-59.

Exclusion Duplicates Scopus 1. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 – 727. Web of Science 1. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194. 2. Meyer, T. E., Chu, L. W., Li, Q., et al., 2012. The association between inflammation-related genes and serum androgen levels in men: the prostate, lung, colorectal, and ovarian study. Prostate [online], 72 (1), 65 - 71.

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3. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 – 727.

NCBI 1. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one- point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 – 402. 2. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 - 727. 3. Pellock, S. J and Redinbo, M. R., Glucuronides in the gut: Sugar-driven symbioses between microbe and host. Journal of Biological Chemistry [online], 292 (21), 8569 – 8576. 4. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 – 727.

Not relevant Scopus 1. Teft, W. A., Welch, S., Lenehan, J., et al., 2015. OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan- based chemotherapy. British Journal of Cancer [online], 112 (5), 857 – 865. 2. Stein, A., Voigt, W and Jordan, K., 2010. Review: Chemotherapy- induced diarrhea: Pathophysiology, frequency and guideline-based management. Therapeutic Advances in Medical Oncology [online], 2 (1), 51 - 63.

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3. Schulz, C., Boeck, S., Heinemann, V., et al., 2009. UGT1A1 genotyping: a predictor of irinotecan-associated side effects and drug efficacy? Anticancer Drugs [online], 20 (10), 867 – 879. 4. Innocenti, F., Kroetz, D. L., Schuetz, E., et al., 2009. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. Journal of Clinical Oncology [online], 27 (16), 2604- 2614. 5. Huang, R and Ratain, M. J., 2009. Pharmacogenetics and pharmacogenomics of anticancer agents. CA Cancer Journal for Clinicians [online], 59 (1), 42 – 55.

NCBI 1. De Mattia, E., Cecchin, E., Montico, M., et al., 2018. Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients. Frontiers in Pharmacology [online], 9 (367), doi: 10.3389/fphar.2018.00367. 2. Etienne-Grimadli, M. C., Boyer, J. C., Thomas, F., et al., 2015. UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice. Fundamental & Clinical Pharmacology [online], 29 (3), 219 – 237. 3. Hahn, R. Z., Antunes, M. V., Verza, S. G., et al., 2018. Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity. Current Medicinal Chemistry [online], doi: 10.2174/0929867325666180622141101. 4. Church, T. R., Haznadar, M., Geisser, M. S., et al., 2010. Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung cancer risk. International Journal of Molecular Epidemiology and Genetics [online], 1 (4), 295 – 309. 5. Strassburg, C. P., Vogel, A., Tukey, R. H., et al., 2002. Polymorphisms of the human UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer. Gut [online], 50 (6), 851 – 856.

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6. Wang, Y and Zheng, Y., 2008. Review on gene polymorphisms of UDP- glucuronosyltransferases and genetic susceptibility of cancer. Journal of Hygiene Research [online], 37 (5), 629 – 632. 7. Routis, E., Charsson, V., Pétain, A., et al., 2008. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. British Journal of Cancer [online], 99 (8), 1239 – 1245. 8. Ando, M., Ando, Y., Sekido, Y., et al., 2002. Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese cancer patients. Japanese Journal of Cancer Research [online], 93 (5), 591 – 597. 9. Girard, H., Butler, L. M., Villeneuve, L., et al., 2008. UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans. Mutation Research [online], 644 (1- 2), 56 – 63. 10. Jada, S. R., Lim, R., Wong, C. I., et al., 2007. Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Science [online], 98 (9), 1461 – 1467. 11. Iqbal, S and Lenz, H. J., 2001. Determinants of prognosis and response to therapy in colorectal cancer. Current Oncology Reports [online], 3 (2), 102 - 108.

Web of Science 1. Innocenti, F., Kroetz, D. L., Schuetz, E., et al., 2009. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. Journal of Clinical Oncology [online], 27 (16), 2604- 2614. 2. Hazama, S., Nagasjima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 – 727.

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3. Schulz-Utermoehl, Spear, M., Pollard, C. R., et al., 2010. In Vitro Hepatic Metabolism of Cediranib, a Potent Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor: Interspecies Comparison and Human Enzymology. Drug Metabolism and Disposition [online], 38 (10), 1688 – 1697. 4. Okumura, M., Iwakiri, T., Takagi, A., et al., 2011. Hepatocyte growth factor suppresses the anticancer effect of irinotecan by decreasing the level of active metabolite in HepG2 cells. Biochemical Pharmacology [online], 82 (11), 1720 – 1730. 5. Mroz, A and Mazerska, Z., 2015. Glucuronidation of antitumour therapeutics - detoxification, mechanism of resistance or prodrug formation? Postȩpy Higieny i Medycyny Doświadczalnej [online], 69, 1462 – 1477. 6. Shelby, M., Fu, W., Badri, P., et al., 2017. Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir. Clinical Pharmacology & Therapeutics [online], 102 (4), 679 – 687.

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Part 2: Abstract screening Inclusion Scopus 1. Suenaga, M., Fuse, N., Yamaguchi, T., et al., 2014. Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Journal of Clinical Pharmacology [online], 54 (5), 495 – 502. 2. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one- point plasma SN-38G/SN-38 concentration ratios as a substitute for

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UGT1A1 genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 – 402. 3. Kim, K-P., Kim, H-S., Sym, S. J., et al., 2013. A UGT1A1*28 and*6 genotype-directed phase i dose-escalation trial of irinotecan with fixed- dose capecitabine in Korean patients with metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology [online], 71 (6), 1609 - 1617. 4. Evarard, A and Mbatchi, L., 2012. Genetic polymorphisms of drug metabolizing enzymes and transporters: The long way from bench to bedside. Current Topics in Medicinal Chemistry [online], 12 (15), 1720 – 1729. 5. Solier, S., Zhang, Y-W., Ballestrero, A., et al., 2012., DNA damage response pathways and cell cycle checkpoints in colorectal cancer: Current concepts and future perspectives for targeted treatment. Current Cancer Drug Targets, 12 (4), 356 – 371. 6. Deenen, M. J., Cats, A., Beijnen, J. H., et al., 2013. Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist [online], 16 (7), 992 - 1005. 7. Li, J and Bluth, M. H., 2011. Pharmacogenomics of drug metabolizing enzymes and transporters: Implications for cancer therapy. Pharmacogenomics and Personalized Medicine [online], 4 (1), 11 – 33. 8. Wu, B., Kulkarni, K., Basu, S., et al., 2011. First-pass metabolism via UDP-glucuronosyltransferase: A barrier to oral bioavailability of phenolics. Journal of Pharmaceutical Sciences [online], 100 (9), 3655 - 3681. 9. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1 * 28 polymorphism. Cancer Science [online], 101 (3), 722 – 727.

210

2. Hirose, K., Kozu, C., Yamashita, K., et al., 2012. Correlation between plasma concentration ratios of SN-38 glucuronide and sn-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene. Oncology Letters [online], 3 (3), 694 – 698. 3. Inoue, K., Sonobe, M., Kawamura, Y., et al., 2013. Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events inCancer Patients Receiving Irinotecan-Based Chemotherapy. Tohoku Journal of Experimental Medicine [online], 229 (2), 107 - 114. 4. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194. 5. Liu, X and Xu, W., 2014. UGT1A1*28 polymorphisms: a potential pharmacological biomarker of irinotecan-based chemotherapies in colorectal cancer. Pharmacogenomics [online], 15 (9), 1171 – 1174.

Exclusion Glucuronides not reported Scopus 1. Labriet, A., De Mattia, E., Cecchin, E., et al., 2017. Improved progression-free survival in irinotecan-treated metastatic colorectal cancer patients carrying the HNF1A coding variant p.I27L. Frontiers in Pharmacology [online], 8 (712), doi: 10.3389/fphar.2017.00712. 2. Mbatchi, L. C., Robert, J., Ychou, M., et al., 2016. Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients. Clinical Pharmacokinetics [online], 55 (9),1145 - 1157. 3. Hou, H-X., Qu, Y-L., Tang, X-S and Tang, Y., 2015.Association of UGT1A1 polymorphisms with irinotecan induced toxicities in advanced colorectal cancer: a Meta-analysis in Asians. Chinese Journal of Cancer Prevention and Treatment [online], 22 (20), 1634 - 1640.

211

4. Park, S. R., Hong, Y. S., Lim, H-S., et al., 2013. Phase i clinical and pharmacokinetic/pharmacogenetic study of a triplet regimen of S- 1/irinotecan/oxaliplatin in patients with metastatic colorectal or gastric cancer. Cancer Chemotherapy and Pharmacology [online], 72 (5), 953 - 964. 5. Xu, J-M., Wang, Y., Ge, F-J., et al., 2013. Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World Journal of Gastroenterology [online], 19 (24), 3899 – 3903. 6. Wang, Y., Shen, L., Xu, N., et al., 2012. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World Journal of Gastroenterology [online], 18 (45), 6635 - 6644. 7. Akiyama, Y., Fujita, K-I., Ishida, H., et al., 2012. Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer. Drug Metabolism and Pharmacokinetics [online], 27 (3), 325 – 335. 8. Meyer, T. E., Chu, L. W., Li, Q., et al., 2012. The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study. Prostate [online], 72 (1), 65 – 71. 9. Ramrez, J., Ratain, M. J and Innocenti, F., 2010. Uridine 5́-diphospho- glucuronosyltransferase genetic polymorphisms and response to cancer chemotherapy. Future Oncology [online], 6 (4), 563 – 585.

NCBI 1. Wang, M., Sun, D. F., Qing, Y., et al., 2013. Polymorphic expression of UDP-glucuronosyltransferase UGTlA gene in human colorectal cancer. PLoS ONE [online], 8 (2), e57045. 2. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2016. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69. 3. Falkowski, S., Woillard, J. B., Postil, D., et al., 2017. Common variants in glucuronidation enzymes and membrane transporters as potential risk

212

factors for colorectal cancer: a case control study. BMC Cancer [online], 17 (1), doi: 10.1186/s12885-017-3728-0. 4. Boyer, J. C., Etienne-Grimaldi, M. C., Thomas, F., et al., 2014. Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan. Bulletin du Cancer [online], 101 (6), 533 – 553. 5. Hung, S. H., Chao, Y., Wu, Y. Y., et al., 2011. Concurrence of UGT1A polymorphism and end-stage renal disease leads to severe toxicities of irinotecan in a patient with metastatic colon cancer. Tumori [online], 97 (2), 243 – 247. 6. Inoue, K., Sonobe, M., Kawamura, Y., et al., 2013. Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. The Tohoku Journal of Experimental Medicine [online], 229 (2), 107 – 114. 7. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one- point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 – 402.

Google Scholar 1. Snozek, C. L., O'Kane, D. J and Algeciras-Schimnich, A., 2009. Pharmacogenetics of solid tumors: directed therapy in breast, lung, and colorectal cancer: a paper from the 2008 william beaumont hospital symposium on molecular pathology. The Journal of Molecular Diagnostics [online], 11 (5), 381 – 389. 2. Onoue, M., Terada, T., Kobayashi, M., et al., 2009. UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients. International Journal of Clinical Oncology [online], 14 (2), 136 – 142. 3. Takano, M., Kato, M., Yoshikawa, T., et al., 2009. Clinical significance of UDP-glucuronosyltransferase 1A1*6 for toxicities of combination chemotherapy with irinotecan and cisplatin in gynecologic cancers: a prospective multi-institutional study. Oncology [online], 76 (5), 315 – 321.

213

4. Fukui, T., Mitsufuji, H., Kubota, M., et al., 2011. Prevalence of topoisomerase I genetic mutations and UGT1A1 polymorphisms associated with irinotecan in individuals of Asian descent. Oncology Letters [online], 2 (5), 923 – 928. 5. Li, M., Wang, Z., Guo, J., et al., 2014. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets and Therapy [online], 23 (7), 1653 – 1661. 6. Wang, J., Joshi, A. D., Corral, R., et al., 2012. Carcinogen metabolism genes, red meat and poultry intake, and colorectal cancer risk. International Journal of Cancer [online], 130 (8), 1898 – 1907. 7. Angstadt, A. Y., Hartman, T. J., Lesko, S. M., et al., 2014.The Effect of UGT1A and UGT2B Polymorphisms on Colorectal Cancer Risk: Haplotype Associations and Gene-Environment Interactions. Genes, Chromosomes & Cancer [online], 53 (6), 454 - 466. 8. Zhang, X., Yin, J. F., Zhang, J., et al., 2017. UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis. Cancer Chemotherapy and Pharmacology [online], 80 (1), 135 – 149. 9. El Bastawisy, A., El-Zeiny, A., Farid, S. F., et al., 2014.UGT1A1*28 Polymorphism in Advanced Colorectal Cancer: The Story Is Not Yet Ended. Journal of Clinical Oncology [online], 32 (3), 53-59.

Disease not specified Scopus 1. Evrard, A and Mbatchi, L., 2012. Genetic polymorphisms of drug metabolizing enzymes and transporters: The long way from bench to bedside. Current Topics in Medicinal Chemistry [online], 12 (15), 1720 – 1729. 2. Deenen, M. J., Cats, A., Beijnen, J. H., Schellens, J. H. M., 2013. Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist [online], 16 (7), 992 - 1005.

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3. Li, J and Bluth, M. H., 2011. Pharmacogenomics of drug metabolizing enzymes and transporters: Implications for cancer therapy. Pharmacogenomics and Personalized Medicine [online], 4 (1), 11 - 33. 4. Walko, C. M and McLeod, H., 2009. Pharmacogenomic progress in individualized dosing of key drugs for cancer patients. Nature Reviews Clinical Oncology [online], 6 (3), 153 – 162. 5. Wu, B., Kulkarni, K., Basu, S., et al., 2011. First-pass metabolism via UDP-glucuronosyltransferase: A barrier to oral bioavailability of phenolics. Journal of Pharmaceutical Sciences [online], 100 (9), 3655 – 3681.

Part 3: Full paper analysis Inclusion Scopus 1. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Science [online], 101 (3), 722 – 727. 2. Meyer, T. E., Chu, L. W., Li, Q., et al., 2012. The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study. Prostate [online], 72 (1), 65 – 71.

Exclusion Abstract provided only Scopus 1. Solier, S., Zhang, Y-W., Ballestrero, A., et al., 2012., DNA damage response pathways and cell cycle checkpoints in colorectal cancer: Current concepts and future perspectives for targeted treatment. Current Cancer Drug Targets, 12 (4), 356 - 371. 2. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass

215

spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194. 3. Suenaga, M., Fuse, N., Yamaguchi, T., et al., 2014. Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Journal of Clinical Pharmacology [online], 54 (5), 495 – 502. 4. Hirose, K., Yamashita, K., Takada, H., et al., 2014. Usefulness of one- point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration. International Journal of Clinical Oncology [online], 19 (2), 397 - 402. 5. Kim, K-P., Kim, H-S., Sym, S. J., et al., 2013. A UGT1A1*28 and*6 genotype-directed phase i dose-escalation trial of irinotecan with fixed- dose capecitabine in Korean patients with metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology [online], 71 (6), 1609 - 1617. 6. Hazama, S., Nagashima, A., Kondo, H., et al., 2010. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1 * 28 polymorphism. Cancer Science [online], 101 (3), 722 – 727.

216

4. Maragon, E., Posocco, B., Mazzega, E., et al., 2015. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study. PLoS ONE [online], 10 (2), e0118194.

Abstracts not provided Google scholar 1. Liu, X and Xu, W., 2014. UGT1A1*28 polymorphisms: a potential pharmacological biomarker of irinotecan-based chemotherapies in colorectal cancer. Pharmacogenomics [online], 15 (9), 1171 – 1174.

Lifestyle Part 1: Title screening Inclusion Scopus 1. Guertin, K. A., Moore, S. C., Sampson, J. N., et al., 2014. Metabolomics in nutritional epidemiology: Identifying metabolites associated with diet and quantifying their potential to uncover diet-disease relations in populations. American Journal of Clinical Nutrition [online], 100 (1), 208 – 217. 2. Deziel, N. C., Strickland, P. T., Platz, E. A., et al., 2011.Comparison of standard methods for assessing dietary intake of benzo[a]pyrene. Cancer Epidemiology Biomarkers and Prevention [online], 20 (5), 962 – 970. 3. de Man, F. M., Goey, A. K. L., van Schaik, R. H. N., et al., 2018. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clinical Pharmacokinetcis [online], 57 (10), 1229 – 1254. 4. Armstrong, H., Bording-Jorgensen, M., Dijk, S., et al., 2018. The complex interplay between chronic inflammation, the microbiome, and cancer:

217

Understanding disease progression and what we can do to prevent it. Cancers [online], 10 (3), doi: 10.3390/cancers10030083. 5. Blázovics, A., Kursinszki, L., Papp, N., et al., 2016. Is professional prescription of a commercially derived dietary supplement in colectomysed patients necessary? European Journal of Integrative Medicine [online], 8 (3), 219 – 226. 6. Huisman, S. A., De Bruijn, P., Ghobadi Moghaddam-Helmantel, I. M., et al., 2016. Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice. British Journal of Pharmacology [online], 173 (5), 804 – 814. 7. Mallick, P., Shah, P., Gandhi, A., et al., 2015. Impact of obesity on accumulation of the toxic irinotecan metabolite, SN-38, in mice. Life Sciences [online], 139, 132 – 138.

Google Scholar 1. Rossi, M., Jahanzaib Anwar, M., Usman A., et al., 2018. Colorectal Cancer and Alcohol Consumption-Populations to Molecules. Cancers [online],10 (2) doi: 10.3390/cancers10020038. 2. Hofmann, J. N., Liao, L. M., Strickland, P. T., et al., 2013. Polycyclic aromatic hydrocarbons: determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study. BMC Cancer [online], 13 (282). doi: 10.1186/1471-2407-13-282. 3. Magalhães, B., Peleteiro, B and Lunet, N., 2012. Dietary patterns and colorectal cancer: systematic review and meta-analysis. European Journal of Cancer Prevention [online], 21 (1), 15 – 23.

4. Sakulterdkiat, T., Srisomsap, C., Udomsangpetch, R., et al., 2012. Curcumin Resistance Induced by Hypoxia in HepG2 Cells Is Mediated by Multidrug-resistance-associated Proteins. Anticancer Research [online], 32 (12), 5337 – 5342. 5. Andrea, A. Y., Berg, A., Zhu, J., et al., 2013. The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk. Cancer [online], 119 (13), 2477 – 2485.

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NCBI 1. Falkowski, S., Woillard, J. B., Postil, D., et al., 2017. Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study. BMC Cancer [online], 17 (1), doi: 10.1186/s12885-017-3728-0.

Excluded Not relevant Scopus 1. Kahle, K., Huemmer, W., Kempf, M., et al., 2007. Polyphenols are intensively metabolized in the human gastrointestinal tract after apple juice consumption. Journal of Agricultural and Food Chemistry [online], 55 (26), 10605 – 10614. 2. Cooke, D., Schwarz, M., Boocock, D., et al., 2006. Effect of cyanidin-3- glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis - Relationship with tissue anthocyanin levels. International Journal of Cancer [online], 119 (9), 2213 – 2220. 3. Kahle, K., Kraus, M., Scheppach, W., et al., 2005. Colonic availability of apple polyphenols--a study in ileostomy subjects. Molecular Nutrition & Food Research [online], 49 (12), 1143 – 1150. 4. Rafter, J., 2003. Probiotics and colon cancer. Bailliere's Best Practice and Research in Clinical Gastroenterology [online], 17 (5), 849 – 859. 5. Campbell, S., Stone, W., Whaley, S., et al., 2003. Development of gamma (γ)-tocopherol as a colorectal cancer chemopreventive agent. Critical Reviews in Oncology/Hematology [online], 47 (3), 249 – 259.

Part 2: Abstract screening Inclusion Scopus 1. Guertin, K. A., Moore, S. C., Sampson, J. N., et al., 2014. Metabolomics in nutritional epidemiology: Identifying metabolites associated with diet

219

and quantifying their potential to uncover diet-disease relations in populations. American Journal of Clinical Nutrition [online], 100 (1), 208 – 217. 2. Deziel, N. C., Strickland, P. T., Platz, E. A., et al., 2011.Comparison of standard methods for assessing dietary intake of benzo[a]pyrene. Cancer Epidemiology Biomarkers and Prevention [online], 20 (5), 962 – 970. 3. Hofmann, J. N., Liao, L. M., Strickland, P. T., et al., 2013. Polycyclic aromatic hydrocarbons: determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study. BMC Cancer [online], 13 (282). doi: 10.1186/1471-2407-13-282.

Exclusion Glucuronides are not reported Google scholar 1. Rossi, M., Jahanzaib Anwar, M., Usman A., et al., 2018. Colorectal Cancer and Alcohol Consumption-Populations to Molecules. Cancers [online],10 (2) doi: 10.3390/cancers10020038. 2. Magalhães, B., Peleteiro, B and Lunet, N., 2012. Dietary patterns and colorectal cancer: systematic review and meta-analysis. European Journal of Cancer Prevention [online], 21 (1), 15 – 23.

Part 3: Full paper analysis Inclusion Scopus 1. Guertin, K. A., Moore, S. C., Sampson, J. N., et al., 2014. Metabolomics in nutritional epidemiology: Identifying metabolites associated with diet and quantifying their potential to uncover diet-disease relations in populations. American Journal of Clinical Nutrition [online], 100 (1), 208 – 217.

220

Google Scholar 1. Hofmann, J. N., Liao, L. M., Strickland, P. T., et al., 2013. Polycyclic aromatic hydrocarbons: determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study. BMC Cancer [online], 13 (282). doi: 10.1186/1471-2407-13-282.

Exclusion Disease unspecified Scopus 1. Deziel, N. C., Strickland, P. T., Platz, E. A., et al., 2011.Comparison of standard methods for assessing dietary intake of benzo[a]pyrene. Cancer Epidemiology Biomarkers and Prevention [online], 20 (5), 962 – 970.

221

Type 2 Diabetes inclusion and exclusion

Genetics Part 1: Title inclusion Scopus 1. Khedher, B. M. R., Abid, M., Jamoussi, K., et al., 2018. Comprehensive insight into functional interaction between GNB3 C825T and eNOS T- 786C, G894T gene polymorphisms and association with susceptibility to diabetic erectile dysfunction. Andrology [online], 6 (6), 865 – 873. 2. Mostafa-Hedeab, G., Mohamed, A. A., Ebid, G. T., et al., 2018. Effect of MATE 1, MATE 2 and OCT1 single nucleotide polymorphisms on metformin action in recently diagnosed egyptian type-2 diabetic patients. Biomedical and Pharmacology Journal [online], 11 (1), 149 – 157. 3. Raudenska, M., Dvorakova, V., Pacal, L., et al., 2017. Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease. Journal of Biochemical and Molecular Toxicology [online], 31 (6), e21891. 4. Dostalek, M., Court, M. H., Hazarika, S., et al., 2011. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl- glucuronide metabolite. Drug Metabolism and Disposition. 39 (3), 448 – 455.

Google scholar 1. Cheung, K. K-T., Lau, E. S., So, W. Y., et al., 2017. Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus – Hong Kong Diabetes Registry. Diabetes Research and Clinical Practice [online], 123, 97 – 105

222

Part 1 exclusion

Duplicates by title

Web of Science

1. Cheng, Y., Wang, L., Iacono, L., et al., 2018. Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β-hydroxysteroid dehydrogenase type-1 inhibitor BMS-823778. British Journal of Clinical Pharmacology [online], 84 (1), 130 - 141. 2. Jeong, H. U., Kim, J. H., Lee, D. Y., et al., 2015. In Vitro Metabolic Pathways of the New Anti-Diabetic Drug Evogliptin in Human Liver Preparations. Molecules [online], 20 (12), 21802 - 21815. 3. Su, H., Boulton, D. W., Barros, A., et al., 2012. Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. Drug Metabolism & Disposition [online], 40 (7), 1345 – 1356.

Not relevant Scopus 1. Cheng, Y., Wang, L., Iacono, L., et al., 2018. Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β-hydroxysteroid dehydrogenase type-1 inhibitor BMS-823778. British Journal of Clinical Pharmacology [online], 84 (1), 130 – 141. 2. Jeong, H. U., Kim, J. H., Lee, D. Y., et al., 2015. In Vitro Metabolic Pathways of the New Anti-Diabetic Drug Evogliptin in Human Liver Preparations. Molecules [online], 20 (12), 21802 – 21815. 3. Su, H., Boulton, D. W., Barros, A., et al., 2012. Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. Drug Metabolism and Disposition [online], 40 (7), 1345 - 1356. 4. Itkonen, M. K., Tornio, A., Neuvonen, M., et al., 2016. Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone. Drug Metabolism and Disposition [online], 44 (8), 1364 - 1371. 223

5. Su, H., Boulton, D. W., Barros, A., et al., 2012. Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. Drug Metabolism and Disposition [online], 40 (7), 1345 – 1356.

Web of Science 1. Abedelhedi, R., Kharrat, N., Maurer, M., et al., 2018. Impact of Clopidogrel Plasmatic Levels, CYP2C19 Polymorphisms and Drug-Drug Interactions on Clinical Outcome in Coronary Artery Disease Patients. Farmacia [online], 66, 135 – 148.

NCBI 1. Jeong, H. U., Kim, J. H., Lee, D. Y., et al., 2015. In Vitro Metabolic Pathways of the New Anti-Diabetic Drug Evogliptin in Human Liver Preparations. Molecules [online], 20 (12), 21802 - 21815.

Part 2: Abstract screening Included Scopus 1. Dostalek, M., Court, M. H., Hazarika, S., et al., 2011. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl- glucuronide metabolite. Drug Metabolism and Disposition [online]. 39 (3), 448 – 455.

Excluded Glucuronide not reported Scopus 1. Khedher, B. M. R., Abid, M., Jamoussi, K., et al., 2018. Comprehensive insight into functional interaction between GNB3 C825T and eNOS T- 786C, G894T gene polymorphisms and association with susceptibility to diabetic erectile dysfunction. Andrology [online], 6 (6), 865 – 873. 224

2. Mostafa-Hedeab, G., Mohamed, A. A., Ebid, G. T., et al., 2018. Effect of MATE 1, MATE 2 and OCT1 single nucleotide polymorphisms on metformin action in recently diagnosed egyptian type-2 diabetic patients. Biomedical and Pharmacology Journal [online], 11 (1), 149 – 157. 3. Raudenska, M., Dvorakova, V., Pacal, L., et al., 2017. Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease. Journal of Biochemical and Molecular Toxicology [online], 31 (6), e21891.

Part 3: Full paper analysis Excluded Glucuronides reported that are not associated to disease Scopus 1. Dostalek, M., Court, M. H., Hazarika, S., et al., 2011. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl- glucuronide metabolite. Drug Metabolism and Disposition. 39 (3), 448 – 455.

225

Lifestyle

Scopus 1. Li, J., Lai, H., Chen, S., et al., 2017. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey. Journal of Diabetes and its Complications [online], 31 (2), 318 – 327.

Google Scholar 1. Mora-Cubillos, X., Tulipani, S., Garcia-Aloy, M., et al., 2015. Plasma metabolomic biomarkers of mixed nuts exposure inversely correlate with severity of metabolic syndrome. Molecular Food Nutrition [online], 59 (12), 2480 – 2490. 2. Zhao. Q., Zhang, A., Zong, W., et al., 2017. Exploring potential biomarkers and determining the metabolic mechanism of type 2 diabetes mellitus using liquid chromatography coupled to high-resolution mass spectrometry. RSC Advances [online], 7, 44186 – 44198.

Part 1 exclusion Duplicates by title Scopus 1. Ji, L., Lai, H., Chen, S., et al., 2017. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey. Journal of Diabetes and its Complications [online], 31 (2), 318 – 327.

Web of Science

1. Ji, L., Lai, H., Chen, S., et al., 2017. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey. Journal of Diabetes and its Complications [online], 31 (2), 318 – 327.

226

NCBI 1. Brouwer-Brolsma, E. M., Brennan, L., Drevon, C. A., et al., 2017. Combining traditional dietary assessment methods with novel metabolomics techniques: present efforts by the Food Biomarker Alliance. Proceedings of the Nutrition Society [online], 76 (4), 619 – 627.

Not relevant Web of Science 1. Anfossi, G., Frascaroli, C., Bonomo, K., et al., 2008. The NPC1L1 inhibitor ezetimibe in the treatment of the dyslipidemia in patients affected by the metabolic syndrome: Evidences and perspectives. Current Enzyme Inhibition [online], 4 (3), 109 – 120.

Part 2: Abstract analysis Inclusion Google scholar 1. Mora-Cubillos, X., Tulipani, S., Garcia-Aloy, M., et al., 2015. Plasma metabolomic biomarkers of mixed nuts exposure inversely correlate with severity of metabolic syndrome. Molecular Food Nutrition [online], 59 (12), 2480 – 2490. Scopus 1. Li, J., Lai, H., Chen, S., et al., 2017. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey. Journal of Diabetes and its Complications [online], 31 (2), 318 – 327. 2. Sun, H., Zhang, S., Zhang, A., et al., 2014. Metabolomic analysis of diet- induced type 2 diabetes using UPLC/MS integrated with pattern recognition approach. PLoS ONE [online]. 9 (3), e93384. 3. Mora-Cubillos, X., Tulipani, S., Garcia-Aloy, M., et al., 2015. Plasma metabolomic biomarkers of mixed nuts exposure inversely correlate with

227

severity of metabolic syndrome. Molecular Food Nutrition [online], 59 (12), 2480 - 2490. 4. Guasch-Ferré, M., Merino, J., Sun, Q., et al., 2017. Dietary Polyphenols, Mediterranean Diet, Prediabetes, and Type 2 Diabetes: A Narrative Review of the Evidence. Oxidative Medicine and Cellular Longevity [online], doi: 10.1155/2017/6723931.

Part 3: Full paper analysis

Inclusion

Scopus

1. Li, J., Lai, H., Chen, S., et al., 2017. Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: the Third National Health and Nutrition Examination Survey. Journal of Diabetes and its Complications [online], 31 (2), 318 – 327.

Google scholar 1. Zhao. Q., Zhang, A., Zong, W., et al., 2017. Exploring potential biomarkers and determining the metabolic mechanism of type 2 diabetes mellitus using liquid chromatography coupled to high-resolution mass spectrometry. RSC Advances [online], 7, 44186 – 44198.

Excluded Glucuronides reported that do not come from human Scopus 1. Sun, H., Zhang, S., Zhang, A., et al., 2014. Metabolomic analysis of diet- induced type 2 diabetes using UPLC/MS integrated with pattern recognition approach. PLoS ONE [online], 9 (3), e93384.

228

Reviews (Literature/systematic) Scopus 1. Guasch-Ferré, M., Merino, J., Sun, Q., et al., 2017. Dietary Polyphenols, Mediterranean Diet, Prediabetes, and Type 2 Diabetes: A Narrative Review of the Evidence. Oxidative Medicine and Cellular Longevity [online], doi: 10.1155/2017/6723931.

229

Parkinson’s disease inclusion and exclusion Genetics Part 1: Title screening Scopus 1. Leuratti, C., Sardina, M., Ventura, P., et al., 2013. Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology [online], 92 (3-4), 207 – 216.

Exclusion Duplicates by title Web of Science 1. Nakajima, M and Yokoi, T., 2005. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metabolism and Pharmacokinetics [online], 20 (4), 227 – 235.

Not relevant Scopus 1. Nakajima, M and Yokoi, T., 2005. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metabolism and Pharmacokinetics [online], 20 (4), 227 – 235.

Web of Science 1. Almeida, L., Loureiro, A. I., Vaz-da-Silva, M., et al., 2010. Chronopharmacology of nebicapone, a new catechol-O- methyltransferase inhibitor. Current Medical Research and Opinion [online], 1097 – 1108. 2. Hajihashemi, S and Geuns, J. M. X., 2013. Radical scavenging activity of steviol glycosides, steviol glucuronide and crude Stevia extracts. Free Radicals and Antioxidants [online], 3 (2), 34 – 39. 3. Laux-Biechlmann, A., Mouheiche, J., Veriepe, J., et al., 2013. Endogenous morphine and its metabolites in mammals: history,

230

synthesis, localization and perspectives. Neuroscience [online], 233, 95 – 117. 4. Gallardo, E., Sarriá, B., Espartero, J. L., et al., 2016. Evaluation of the Bioavailability and Metabolism of Nitroderivatives of Hydroxytyrosol Using Caco-2 and HepG2 Human Cell Models. Journal of Agricultural and Food Chemistry [online], 64 (11), 2289 – 2297.

NCBI 1. Martignoni, E., Cosentino, M., Ferrari, M., et al., 2005. Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Neurology [online], 65 (11), 1820 – 1822.

Part 2: Abstract screening Excluded Glucuronides not reported 1. Leuratti, C., Sardina, M., Ventura, P., et al., 2013. Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology [online], 92 (3-4), 207 – 216.

Lifestyle Part 1: Title screening Exclusion Duplicates by title Web of Science 1. Almeida, L., Loureiro, A. I., Vaz-da-Silva, M., et al., 2010. Chronopharmacology of nebicapone, a new catechol-O- methyltransferase inhibitor. Current Medical Research and Opinion [online], 1097 – 1108. 2. Hajihashemi, S and Geuns, J. M. X., 2013. Radical scavenging activity of steviol glycosides, steviol glucuronide and crude Stevia extracts. Free Radicals and Antioxidants [online], 3 (2), 34 – 39.

231

3. Leuratti, C., Sardina, M., Ventura, P., et al., 2013. Disposition and metabolism of safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology [online], 92 (3-4), 207 – 216. 4. Laux-Biechlmann, A., Mouheiche, J., et al., 2013. Endogenous morphine and its metabolites in mammals: history, synthesis, localization and perspectives. Neuroscience [online], 233, 95 – 117.

Not relevant Web of Science 1. Angeloni, C., Malaguti, M., Barbalace, M. C., et al., 2017. Bioactivity of olive oil phenols in neuroprotection. International Journal of Molecular Sciences [online], 18 (11), doi: 10.3390/ijms18112230. 2. Speciale, A., Chirafisi, J., Saija, A., et al., 2011. Nutritional antioxidants and adaptive cell responses: An update. Current Molecular Medicine [online], 11 (9), 770 – 789. 3. Gallardo, E., Sarriá, B., Espartero, J. L., et al., 2016. Evaluation of the Bioavailability and Metabolism of Nitroderivatives of Hydroxytyrosol Using Caco-2 and HepG2 Human Cell Models. Journal of Agricultural and Food Chemistry [online], 64 (11), 2289 – 2297.

232

Prostate cancer inclusion and exclusion Genetics Part 1: Inclusion NCBI 1. Grant, D. J., Hoyo, C., Oliver, S. D., et al., 2013. Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. Genetic Testing and Molecular Biomarkers [online], 17 (1), 3 – 9. 2. Lévesque, É., Laverdière, I., Lacombe, L., et al., 2014. Importance of 5α-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer. Clinical Cancer Research [online], 20 (3), 576 – 584. 3. Lévesque, É., Huang, S. P, Audet-Walsh, É., et al., 2015. Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression. Clinical Cancer Research [online], 19 (3), 699 – 709. 4. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2016. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69.

5. Karatzas, A., Giannatou, E., Tzortzis, V., et al., 2010. Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men. Cancer Epidemiology [online], 34 (3), 345 – 349. 6. Hu, D. G, Gardner-Stephen, D., Severi, G., et al, 2010. A novel polymorphism in a forkhead box A1 (FOXA1) binding site of the human UDP glucuronosyltransferase 2B17 gene modulates promoter activity and is associated with altered levels of circulating androstane-3α,17β- diol glucuronide. Molecular Pharmacology [online], 78 (4), 714 – 722. 7. Meyer, T. E., Chu, L. W., Li, Q., et al., 2012. The association between inflammation-related genes and serum androgen levels in men: the

233

prostate, lung, colorectal, and ovarian study. Prostate [online], 72 (1), 65 – 71. 8. Nadeau, G., Bellemare, J., Audet-Walsh, É., et al., 2011. Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer. The Journal of Clinical Endocrinology and Metabolism [online], 96 (9), 1550 – 1557. 9. Laverdière, I., Flageole, C., Audet-Walsh, É., et al., 2015. The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy. Endocrine-related Cancer [online], 22 (1), 77 – 85.

Google scholar 1. Grant, D. J., Hoyo, C., Oliver, S. D., et al., 2013. Association of uridine diphosphate glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. Genetic Testing and Molecular Biomarkers [online], 17 (1), 3 – 9. 2. Karatzas, A., Giannatou, E., Tzortzis, V., et al., 2010. Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men. Cancer Epidemiology [online], 34 (3), 345 – 349. 3. Gauthier-Landry, L., Bélanger, A and Barbier, O., 2015. Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution. The Journal of Steroid Biochemistry and Molecular Biology [online], 145, 187 – 192. 4. Mononen, N and Schleutker, J., 2009. Polymorphisms in genes involved in androgen pathways as risk factors for prostate cancer. The Journal of Urology [online], 181 (4), 1541 – 1549. 5. Setlur, S. R., Chen, C. X., Hossain, R. R., et al., 2010. Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer. Cancer Epidemiology, Biomarkers & Prevention [online], 19 (1), 229 – 239.

234

6. McNamara, K. M., Nakamura, Y., Miki, Y., et al., 2013. Phase two steroid metabolism and its roles in breast and prostate cancer patients. Frontiers in Endocrinology [online], 4 (116), doi: 10.3389/fendo.2013.00116. 7. Fujimoto, N., Kubo, T., Inatomi, H., et al., 2013. Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation. Prostate Cancer and Prostatic Diseases [online], 16 (4), 336 – 340. 8. Vidal, A. C., Tucker, C., Schlidkraut, J. M., et al., 2013. Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study. BMC Cancer [online], 13 (556), doi: 10.1186/1471-2407-13-556. 9. Eaton, N. E., Reeves, G. K., Appleby, P. N., et al., 1999. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. British Journal of Cancer [online], 80 (7), 930 – 934. 10. Travis, R. C., Key, T. J., Allen, N. E., et al., 2007. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer [online], 121 (6), 1331 – 1338.

Exclusion Part 1: Not relevant Scopus 1. Weisenburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154.

NCBI 1. Church, T. R., Haznadar, M., Geisser, M. S., et al., 2010. Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung cancer risk.

235

International Journal of Molecular Epidemiology and Genetics [online], 1 (4), 295 – 309. 2. Bushey, R. T., Chen, G., Blevins-Primeau, A. S., et al., 2011. Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenetics and Genomics [online], 21 (2), 55 – 65.

3. Hayes, V. M., Severi, G., Padilla, E. J., et al., 2007. 5alpha-Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. International Journal of Cancer [online], 120 (4), 776 – 780. 4. Karypidis, A. H., Olsson, M., Andersson, S. O., et al., 2008. Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate. The Pharmacogenetics Journal [online], 8 (2), 147 – 151. 5. Febbo, P. G., Kantoff, P. W., et al., 1999. The V89L polymorphism in the 5alpha-reductase type 2 gene and risk of prostate cancer. Cancer Research [online], 59 (23), 5878 – 5881. 6. Allen, N. E., Reichardt, J. K., Nguyen, H., et al., 2003. Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men. Cancer Epidemiology, Biomarkers & Prevention [online], 12 (6), 578 – 581. 7. Chu, L. W., Zhu, Y., Yu, K., et al., 2008. Correlation between circadian gene variants and serum levels of sex steroids and insulin-like growth factor-I. Cancer Epidemiology, Biomarkers & Prevention [online], 17 (11), 3268 – 3273.

8. Low, Y. L., Taylor, J. I., Grace, P. B., et al., 2005. Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men. Journal of Nutrition [online], 135 (11), 2680 – 2686. 9. Jakobsoon, J., Ekström, L., Inotsume, N., et al., 2006. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism.

236

The Journal of Clinical Endocrinology and Metabolism [online], 91 (2), 687 – 693.

Duplicates by title Web of Science 1. Weisenburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154.

NCBI 1. Gallagher, C. J., Kadlubar, F. F., Muscat, J. E., et al., 2007. The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians. Cancer Detection and Prevention [online], 31 (4), 310 – 315.

2. Allen, N. E., Reichardt, J. K., Nguyen, H., et al., 2003. Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men. Cancer Epidemiology, Biomarkers & Prevention [online], 12 (6), 578 – 581. 3. Allen, N. E., Forrest, M. S and Key, T. J., 2001. The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men. Cancer Epidemiology, Biomarkers & Prevention [online], 185 – 189. 4. Wang, Y and Zheng, Y., 2008. Review on gene polymorphisms of UDP- glucuronosyltransferases and genetic susceptibility of cancer. Wei Sheng Yan Jiu (Journal of Hygiene Research) [online], 37 (5), 629 – 632. 5. Macleod, S. L., Nowell, S., Plaxco, J., et al., 2000. An allele-specific polymerase chain reaction method for the determination of the D85Y polymorphism in the human UDP-glucuronosyltransferase 2B15 gene in a case-control study of prostate cancer. Annals of Surgical Oncology [online], 7 (10), 777 – 782.

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Google Scholar 1. Gallagher, C. J., Kadlubar, F. F., Muscat, J. E., et al., 2007. The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians. Cancer Detection and Prevention [online], 31 (4), 310 – 315.

2. Park, J., Chen, L., Ratnashinge, L., et al., 2006. Deletion polymorphism of UDP-glucuronosyltransferase 2B17 and risk of prostate cancer in African American and Caucasian men. Cancer Epidemiology, Biomarkers & Prevention [online], 15 (8), 1473 – 1478. 3. Gallagher, C. J., Kadlubar, F. F., Muscat, J. E., et al., 2007. The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians. Cancer Detection and Prevention [online], 31 (4), 310 – 315. 4. Hsing, A. W., Chen, C., Chokkalingam, A. P., et al., 2001. Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population- based case-control study. Cancer Epidemiology, Biomarkers & Prevention [online], 10 (10), 1077 – 1082.

5. Chu, L. W., Zhu, Y., Yu, K., et al., 2008. Correlation between circadian gene variants and serum levels of sex steroids and insulin-like growth factor-I. Cancer Epidemiology, Biomarkers & Prevention [online], 17 (11), 3268 – 3273. 6. Singh, P. B., Matanhelia, S. S and Martin, F. L., 2008. A potential paradox in prostate adenocarcinoma progression: oestrogen as the initiating driver. European Journal of Cancer [online], 44 (7), 928 – 936. 7. Travis, R. C., Key, T. J., Allen, N. E., et al., 2007. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer [online], 121 (6), 1331 – 1338.

238

Part 2 abstract analysis: Inclusion: NCBI 1. Grant, D. J., Hoyo, C., Oliver, S. D., et al., 2013. Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. Genetic Testing and Molecular Biomarkers [online], 17 (1), 3 – 9. 2. Lévesque, É., Laverdière, I., Lacombe, L., et al., 2014. Importance of 5α- reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer. Clinical Cancer Research [online], 20 (3), 576 – 584. 3. Nadeau, G., Bellemare, J., Audet-Walsh, É., et al., 2011. Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer. The Journal of Clinical Endocrinology and Metabolism [online], 96 (9), 1550 – 1557. 4. Hsing, A. W., Chen, C., Chokkalingam, A. P., et al., 2001. Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population- based case-control study. Cancer Epidemiology, Biomarkers & Prevention [online], 10 (10), 1077 – 1082. 5. Macleod, S. L., Nowell, S., Plaxco, J., et al., 2000. An allele-specific polymerase chain reaction method for the determination of the D85Y polymorphism in the human UDP-glucuronosyltransferase 2B15 gene in a case-control study of prostate cancer. Annals of Surgical Oncology [online], 7 (10), 777 – 782. 6. Eaton, N. E., Reeves, G. K., Appleby, P. N., et al., 1999. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. British Journal of Cancer [online], 80 (7), 930 – 934.

Google scholar 1. Gauthier-Landry, L., Bélanger, A and Barbier, O., 2015. Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in

239

androgen metabolism and prostate cancer evolution. The Journal of Steroid Biochemistry and Molecular Biology [online], 145, 187 – 192. 2. Setlur, S. R., Chen, C. X., Hossain, R. R., et al., 2010. Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer. Cancer Epidemiology, Biomarkers & Prevention [online], 19 (1), 229 – 239.

Exclusion: Glucuronides unreported NCBI 1. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2016. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69. 2. Karatzas, A., Giannatou, E., Tzortzis, V., et al., 2010. Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men. Cancer Epidemiology [online], 34 (3), 345 – 349. 3. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2016. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69. 4. Meyer, T. E., Chu, L. W., Li, Q., et al., 2012. The association between inflammation-related genes and serum androgen levels in men: the prostate, lung, colorectal, and ovarian study. Prostate [online], 72 (1), 65 – 71.

5. Park, J., Chen, L., Ratnashinge, L., et al., 2006. Deletion polymorphism of UDP-glucuronosyltransferase 2B17 and risk of prostate cancer in African American and Caucasian men. Cancer Epidemiology, Biomarkers & Prevention [online], 15 (8), 1473 – 1478. 6. Gallagher, C. J., Kadlubar, F. F., Muscat, J. E., et al., 2007. The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians. Cancer Detection and Prevention [online], 31 (4), 310 – 315.

240

Google scholar 1. Karatzas, A., Giannatou, E., Tzortzis, V., et al., 2010. Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men. Cancer Epidemiology [online], 34 (3), 345 – 349. 2. Mononen, N and Schleutker, J., 2009. Polymorphisms in genes involved in androgen pathways as risk factors for prostate cancer. The Journal of Urology [online], 181 (4), 1541 – 1549. 3. McNamara, K. M., Nakamura, Y., Miki, Y., et al., 2013. Phase two steroid metabolism and its roles in breast and prostate cancer patients. Frontiers in Endocrinology [online], 4 (116), doi: 10.3389/fendo.2013.00116. 4. Fujimoto, N., Kubo, T., Inatomi, H., et al., 2013. Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation. Prostate Cancer and Prostatic Diseases [online], 16 (4), 336 – 340. 5. Vidal, A. C., Tucker, C., Schlidkraut, J. M., et al., 2013. Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study. BMC Cancer [online], 13 (556), doi: 10.1186/1471-2407-13-556.

Part 3 inclusion NCBI 1. Grant, D. J., Hoyo, C., Oliver, S. D., et al., 2013. Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. Genetic Testing and Molecular Biomarkers [online], 17 (1), 3 – 9. 2. Lévesque, É., Laverdière, I., Lacombe, L., et al., 2014. Importance of 5α- reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer. Clinical Cancer Research [online], 20 (3), 576 – 584. 3. Nadeau, G., Bellemare, J., Audet-Walsh, É., et al., 2011. Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating

241

steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer. The Journal of Clinical Endocrinology and Metabolism [online], 96 (9), 1550 – 1557.

4. Hsing, A. W., Chen, C., Chokkalingam, A. P., et al., 2001. Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population- based case-control study. Cancer Epidemiology, Biomarkers & Prevention [online], 10 (10), 1077 – 1082.

Exclusion Abstract provided only: Google Scholar 1. Gauthier-Landry, L., Bélanger, A and Barbier, O., 2015. Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution. The Journal of Steroid Biochemistry and Molecular Biology [online], 145, 187 – 192.

Reviews (Literature/systematic) 1. Eaton, N. E., Reeves, G. K., Appleby, P. N., et al., 1999. Endogenous sex hormones and prostate cancer: a quantitative review of prospective studies. British Journal of Cancer [online], 80 (7), 930 – 934.

242

Lifestyle Part 1: Title screening Inclusion Google scholar 1. Suzuki, R., Allen, N. E., Appleby, P. N., et al., 2009. Lifestyle factors and serum androgens among 636 middle aged men from seven countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes & Control [online], 20 (6), 811 – 821. 2. DeVere White, R. W., Tsodikov, A., Stapp, E. C., et al., 2010. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutrition and Cancer [online], 62 (8), 1036 – 1043. 3. Liao, C. H., Li, H. Y., Chung, S. D., et al., 2012. Significant association between serum dihydrotestosterone level and prostate volume among Taiwanese men aged 40-79 years. The Aging Male [online], 15 (1), 28 – 33. 4. Grainger, E. M., Moran, N. E., Francis, D. M., et al., 2018. A novel tomato-soy juice induces a dose-response increase in urinary and plasma phytochemical biomarkers in men with prostate cancer. The Journal of Nutrition [online], 149 (1), 26 – 35. 5. Arthur. R., Rohrmann, S., Møller, H., et al., 2017. Pre-diabetes and serum sex steroid hormones among US men. Andrology [online], 5 (1), 49 – 57. 6. DeVere White, R. W., Tsodikov, A., et al., 2010. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutrition and Cancer [online], 62 (8), 1036 – 1043. 7. Grainger, E. M., Moran, N. E., Francis, D. M., et al., 2018. A novel tomato-soy juice induces a dose-response increase in urinary and plasma phytochemical biomarkers in men with prostate cancer. The Journal of Nutrition [online], 149 (1), 26 – 35. 8. Setlur, S. R., Chen, C. X., Hossain, R. R., et al., 2010. Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of

243

prostate cancer. Cancer Epidemiology, Biomarkers & Prevention [online], 19 (1), 229 – 239.

NCBI 1. Arthur. R., Rohrmann, S., Møller, H., et al., 2017. Pre-diabetes and serum sex steroid hormones among US men. Andrology [online], 5 (1), 49 – 57.

Exclusion Duplicates Web of Science 1. Weisenburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154.

NCBI 1. Weisenburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154. 2. Grant, D. J., Hoyo, C., Oliver, S. D., et al., 2013. Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. Genetic Testing and Molecular Biomarkers [online], 17 (1), 3 – 9.

Not relevant Scopus 1. Weisenburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154.

244

NCBI 1. Wu, A. H., Whittemore, A. S., Kolonel, L. N., et al., 2001. Lifestyle determinants of 5alpha-reductase metabolites in older African-American, white, and Asian-American men. Cancer Epidemiology, Biomarkers & Prevention [online], 10 (5), 533 – 538.

Google scholar 1. Platz, E. A., Rimm, E. B., Willet, W. C., et al., 2000. Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals. Journal of the National Cancer Institute [online], 92 (24), 2009 – 2017. 2. Travis, R. C., Key, T. J., Allen, N. E., et al., 2007. Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer [online], 121 (6), 1331 – 1338. 3. Allen, N. E., Appleby, P. N., Davey, G. K., et al., 2000. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men. British Journal of Cancer [online], 83 (1), 95 – 97. 4. Kristal, A. R., Schenk, J. M., Song, Y., et al., 2008. Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial. American Journal of Epidemiology [online], 168 (12), 1416 – 1424. 5. Nan, H. M., Kim, H., Lim, H. S., et al., 2001. Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations. Carcinogenesis [online], 22 (5), 787 – 793. 6. Joseph, M. A., Wei, J. T., Harlow, S. D., et al., 2002. Relationship of serum sex-steroid hormones and prostate volume in African American men. Prostate [online], 53 (4), 322 – 329. 7. Mohr, B. A., Feldman, H. A., Kalish, L. A., et al., 2001. Are serum hormones associated with the risk of prostate cancer? Prospective results from the Massachusetts Male Aging Study. Urology [online], 57 (5), 930 – 935.

245

8. Wang, C., Christenson, P and Swerdloff, R., 2007. Clinical Relevance of Racial and Ethnic Differences in Sex Steroids. The Journal of Clinical Endocrinology & Metabolism [online], 92 (7), 2433 – 2435. 9. Marks, L. S., Hess, D. L., Dorey, F. J., et al., 2006. Prostatic tissue testosterone and dihydrotestosterone in African-American and white men. Urology [online], 68 (2), 337 – 341.

Part 2: Abstract screening Inclusion Google Scholar 1. Suzuki, R., Allen, N. E., Appleby, P. N., et al., 2009. Lifestyle factors and serum androgens among 636 middle aged men from seven countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes & Control [online], 20 (6), 811 – 821.

Exclusion Glucuronides unreported Google Scholar 1. Arthur. R., Rohrmann, S., Møller, H., et al., 2017. Pre-diabetes and serum sex steroid hormones among US men. Andrology [online], 5 (1), 49 – 57. 2. DeVere White, R. W., Tsodikov, A., et al., 2010. Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutrition and Cancer [online], 62 (8), 1036 – 1043. 3. Grainger, E. M., Moran, N. E., Francis, D. M., et al., 2018. A novel tomato-soy juice induces a dose-response increase in urinary and plasma phytochemical biomarkers in men with prostate cancer. The Journal of Nutrition [online], 149 (1), 26 – 35. 4. Setlur, S. R., Chen, C. X., Hossain, R. R., et al., 2010. Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of

246

prostate cancer. Cancer Epidemiology, Biomarkers & Prevention [online], 19 (1), 229 – 239.

Disease not specified Google Scholar 1. Liao, C. H., Li, H. Y., Chung, S. D., et al., 2012. Significant association between serum dihydrotestosterone level and prostate volume among Taiwanese men aged 40-79 years. The Aging Male [online], 15 (1), 28 – 33.

Part 3: Inclusion Google Scholar 1. Suzuki, R., Allen, N. E., Appleby, P. N., et al., 2009. Lifestyle factors and serum androgens among 636 middle aged men from seven countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes & Control [online], 20 (6), 811 – 821.

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Breast cancer inclusion and exclusion Genetics Part 1: Title screening Inclusion Scopus 1. Johnson, N., De Ieso, P., et al., 2016. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic Leukemia, Breast, and Lung Cancer. Cancer Research [online], 76 (6), 1485 – 1493. 2. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 3. Johnson, N., Walker, K., Gibson, L.J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 669. 4. Figueroa, J. D and Brinton, L. A., 2012. Unraveling genes, hormones, and breast cancer. Journal of the National Cancer Institute [online], 104 (9), 641 – 642. 5. Mürdter, T. E., Schroth, W., Bacchus-Gerybadze, L., et al., 2011. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase i and II enzymes on their concentration levels in plasma. Clinical Pharmacology and Therapeutics [online], 89 (5), 1 – 10. 6. Sun, D., Chen, G., Dellinger, R. W., et al., 2010. Characterization of 17- dihydroexemestane glucuronidation: Potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenetics and Genomics [online], 20 (10), 575 – 585. 7. Sutiman, N., Lim, J. S. L., Muerdter, T. E., et al., 2016. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clinical Pharmacokinetics [online], 55 (10), 1239 – 1250.

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NCBI 1. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2013. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69. 2. Johnson, N., Dudbridge, F., Orr, N., et al., 2014. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study. Breast Cancer Research [online], 16 (3), doi: 10.1186/bcr3662. 3. Johnson, N., Walker, K., Gibson, L. J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 659. 4. Lang, T., Justenhoven, C., Winter, S., et al., 2011. The earwax- associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancerrisk in Europeans. Breast Cancer Research and Treatment [online], 129 (3), 993 – 999. 5. Lee, E., Schumacher, F., Lewinger, J. P., et al., 2011. The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort. Breast Cancer Research [online], 13 (2), doi: 10.1186/bcr2859. 6. Yong, M., Schwartz, S. M., Atkinson, C., et al., 2010. Associations between polymorphisms in glucuronidation and sulfation enzymes and mammographic breast density in premenopausal women in the United States. Cancer Epidemiology, Biomarkers and Prevention [online], 19 (2), 537 – 546. 7. Wang, Y and Zhen, Y., 2008. Review on gene polymorphisms of UDP- glucuronosyltransferases and genetic susceptibility of cancer. Wei Sheng Yan Jiu (Journal of Hygiene Research), 37 (5), 629 – 632.

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Exclusion Duplicates by title Web of Science 1. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 2. Bushey, R. T., Chen, G., Blevins-Primeau, A. S., et al., 2011. Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenetics and Genomics [online], 21 (2), 55 – 65. 3. Miura, M., Kagaya, H., Satoh, S., et al., 2008. Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Therapeutic Drug Monitoring [online], 30 (5), 559 – 564. 4. Innocenti, F., Iyer, L., Ramírez, J., et al., 2001. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metabolism and Disposition [online], 29 (5), 686 – 692.

NCBI 1. Johnson, N., Leso, P., Migliorini, G., et al., 2016. Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer. Cancer Research [online], 76 (6), 1485 – 1493. 2. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 3. Sun, D., Jones, N. R., Manni, A., et al., 2013. Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prevention Research [online], 6 (7), 719 – 730.

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4. Figueora, J. D and Brinton, L. A., 2012. Unraveling genes, hormones, and breast cancer. Journal of National Cancer Institute [online], 104 (9), 641 – 642. 5. Johnson, N., Walker, K., Gibson, L.J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 669.

Google scholar 1. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 2. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 3. Sutiman, N., Lim, J. S. L., Muerdter, T. E., et al., 2016. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clinical Pharmacokinetics [online], 55 (10), 1239 – 1250.

Not relevant Scopus 1. Bushey, R. T., Chen, G., Blevins-Primeau, A. S., et al., 2011. Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenetics and Genomics [online], 21 (2), 55 – 65. 2. Innocenti, F., Kroetz, D. L., Schuetz, E., et al., 2009. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. Journal of Clinical Oncology [online], 27 (16), 2604 – 2614. 3. Miura, M., Kagaya, H., Satoh, S., et al., 2008. Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic

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glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Therapeutic Drug Monitoring [online], 30 (5), 559 – 564.

Web of science 1. Iyer, D. R and Parani, M., 2018. Screening of patients with Gilbert's Syndrome from South India identifies UGT1A1*28 as the most predominant mutation in UGT1A1 gene. Research Journal of Biotechnology [online], 13 (4), 37 – 40. 2. Mroz, A and Mazerska, Z., 2015. Glucuronidation of antitumour therapeutics - detoxification, mechanism of resistance or prodrug formation? Postepy Higieny I Medycyny Doswiadczalnej (Hygiene Stands and Experimental Medicine) [online], 69, 1462 – 1477.

No keyword(s) mentioned Scopus 1. Sun, D., Chen, G., Dellinger, R. W., et al., 2006. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Research [online], 8 (4), DOI: 10.1186/bcr1539.

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2. Guillemette, C., Bélanger, A and Lépine, J., 2004. Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: An overview. Breast Cancer Research [online], 6 (6), 246 – 254. 3. Innocenti, F., Iyer, L., Ramírez, J., et al., 2001. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metabolism and Disposition [online], 29 (5), 686 – 692. 4. Sun, D., Jones, N. R., Manni, A., et al., 2013. Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prevention Research [online], 6 (7), 719 – 730.

NCBI 1. Tsezou, A., Tzetis, M., Giannatou, E., et al., 2007. Genetic polymorphisms in the UGT1A1 gene and breast cancer risk in Greek women. Genetic Testing and Molecular Biomarkers [online], 11 (3), 303 – 306. 2. Guillemette, C., Millikan, R. C., Newmann, B., et al., 2000. Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Cancer Research [online], 60, 950 – 956. 3. Cheng, T. C., Chen, S. T., Huang, C. S., et al., 2005. Breast cancer risk associated with genotype polymorphism of the catechol estrogen- metabolizing genes: a multigenic study on cancer susceptibility. International Journal of Cancer Research [online], 113 (3), 345 – 353. 4. Raftogianis, R., Creveling, C., Weinshilboum, R., et al., 2000. Estrogen metabolism by conjugation. Journal of the National Cancer Institute. Monographs [online], 113 – 124. 5. Grant , D. J and Bell, D. A., 2000. Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: susceptibility to oxidative damage and cancer? Molecular Carcinogenesis 29 (4), 198 – 204. 6. Wang, Y and Zhen, Y., 2008. Review on gene polymorphisms of UDP- glucuronosyltransferases and genetic susceptibility of cancer. Wei Sheng Yan Jiu (Journal of Hygiene Research), 37 (5), 629 – 632.

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Google scholar 1. Guillemette, C., De Vivo, I., Hankinson, S. E., et al., 2001. Association of Genetic Polymorphisms in UGT1A1 with Breast Cancer and Plasma Hormone Levels. Cancer Epidemiology, Biomarkers & Prevention [online], 10 (6), 711 – 714. 2. Sparks, R., Ulrich, C. M., Bigler, J., 2004. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients. Breast Cancer Research [online], 6, 488 – 498. 3. Shatalova, E. G., Walther, S. E., Favorova, O. O., et al., 2005. Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study. Breast Cancer Research [online], 7, 909 – 921.

Part 2 abstract screening Inclusion Scopus 1. Johnson, N., De Ieso, P., Migliorini, G., Orr, N., et al., 2016. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic Leukemia, Breast, and Lung Cancer. Cancer Research [online], 76 (6), 1485 – 1493. 2. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269. 3. Johnson, N., Walker, K., Gibson, L.J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 669. 4. Mürdter, T.E., Schroth, W., Bacchus-Gerybadze, L., et al., 2011. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase i and II enzymes on their

254

concentration levels in plasma. Clinical Pharmacology and Therapeutics [online], 89 (5), 1 – 10. 5. Sun, D., Chen, G., Dellinger, R. W., et al., 2010. Characterization of 17- dihydroexemestane glucuronidation: Potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenetics and Genomics [online], 20 (10), 575 – 585.

6. Sutiman, N., Lim, J. S. L., Muerdter, T. E., et al., 2016. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clinical Pharmacokinetics [online], 55 (10), 1239 – 1250.

NCBI 1. Johnson, N., Walker, K., Gibson, L.J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 669.

Exclusion Glucuronides not reported Scopus 1. Figueroa, J. D and Brinton, L. A., 2012. Unraveling genes, hormones, and breast cancer. Journal of the National Cancer Institute [online], 104 (9), 641 – 642.

NCBI 1. Johnson, N., Dudbridge, F., Orr, N., et al. ., 2014. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study. Breast Cancer Research [online], 16 (3), doi: 10.1186/bcr3662. 2. Lang, T., Justenhoven, C., Winter, S., et al., 2011. The earwax- associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancerrisk in Europeans. Breast Cancer Research and Treatment [online], 129 (3), 993 – 999.

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3. Lee, E., Schumacher, F., Lewinger, J. P., et al., 2011. The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort. Breast Cancer Research [online], 13 (2), doi: 10.1186/bcr2859.

Disease not specified NCBI 1. Hu, D. G., Mackenzie, P. I., McKinnon, R. A., et al., 2013. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metabolism Reviews [online], 48 (1), 47 – 69. 2. Yong, M., Schwartz, S. M., Atkinson, C., et al., 2010. Associations between polymorphisms in glucuronidation and sulfation enzymes and mammographic breast density in premenopausal women in the United States. Cancer Epidemiology, Biomarkers and Prevention [online], 19 (2), 537 – 546.

Part 3:Full paper screening Inclusion Scopus 1. Johnson, N., De Ieso, P., Migliorini, G., et al., 2016. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic Leukemia, Breast, and Lung Cancer. Cancer Research [online], 76 (6), 1485 – 1493. 2. Sutiman, N., Lim, J. S. L., Muerdter, T. E., et al., 2016. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clinical Pharmacokinetics [online], 55 (10), 1239 – 1250. 3. Romero-Lorca, A., Novillo, A., Gaibar, M., et al., 2015. Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS ONE [online], 10 (7), e0132269.

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Full text unavailable Scopus 1. Mürdter, T. E., Schroth, W., Bacchus-Gerybadze, L., et al., 2011. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase i and II enzymes on their concentration levels in plasma. Clinical Pharmacology and Therapeutics [online], 89 (5), 1 – 10.

Cell line studies Scopus 1. Sun, D., Chen, G., Dellinger, R. W., et al., 2010. Characterization of 17- dihydroexemestane glucuronidation: Potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenetics and Genomics [online], 20 (10), 575 – 585.

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Lifestyle Part 1: Title screening Inclusion Google scholar 1. Yong, M., Schwartz, S. M., Atkinson, C., et al., 2010. Associations between polymorphisms in glucuronidation and sulfation enzymes and mammographic breast density in premenopausal women in the United States. Cancer Epidemiology, Biomarkers and Prevention [online], 19 (2), 537 – 546. 2. Ávila-Gálves, M. Á., Espín, J. C and González-Sarrías, A., 2018. Physiological Relevance of the Antiproliferative and Estrogenic Effects of Dietary Polyphenol Aglycones versus Their Phase-II Metabolites on Breast Cancer Cells: A Call of Caution. Journal of Agriculture and Food Chemistry [online], 66 (32), 8547 – 8555. 3. Armitage, E. G and Barbas, C., 2014. Metabolomics in cancer biomarker discovery: current trends and future perspectives. Journal of Pharmaceutical and Biomedical Analysis [online], 87, 1 – 11. 4. Ávila-Gálves, M. Á., Espín, J. C and González-Sarrías, A., 2018. Physiological Relevance of the Antiproliferative and Estrogenic Effects of Dietary Polyphenol Aglycones versus Their Phase-II Metabolites on Breast Cancer Cells: A Call of Caution. Journal of Agriculture and Food Chemistry [online], 66 (32), 8547 – 8555.

Exclusion Duplicates by title Web of Science 1. Weisburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154. NCBI 1. Weisburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their

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prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154. 2. Johnson, N., Walker, K., Gibson, L.J., et al., 2012. CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute [online], 104 (9), 657 – 669.

Not relevant Scopus 1. Weisburger, J. H and Chung, F-L., 2002. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food and Chemical Toxicology [online], 40 (8), 1145 – 1154.

Google scholar 1. Alaejos, M. S., Pino, V and Afonso, A. M., 2008. Metabolism and toxicology of heterocyclic aromatic amines when consumed in diet: influence of the genetic susceptibility to develop human cancer. A review. Food Research International [online], 41 (4), 347 – 340.

Part 2: Abstract screening Inclusion Google Scholar 1. Ávila-Gálves, M. Á., Espín, J. C and González-Sarrías, A., 2018. Physiological Relevance of the Antiproliferative and Estrogenic Effects of Dietary Polyphenol Aglycones versus Their Phase-II Metabolites on Breast Cancer Cells: A Call of Caution. Journal of Agriculture and Food Chemistry [online], 66 (32), 8547 – 8555.

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Exclusion Glucuronides not reported Google Scholar 1. Armitage, E. G and Barbas, C., 2014. Metabolomics in cancer biomarker discovery: current trends and future perspectives. Journal of Pharmaceutical and Biomedical Analysis [online], 87, 1 – 11.

Disease not specified NCBI 1. Yong, M., Schwartz, S. M., Atkinson, C., et al., 2010. Associations between polymorphisms in glucuronidation and sulfation enzymes and mammographic breast density in premenopausal women in the United States. Cancer Epidemiology, Biomarkers and Prevention [online], 19 (2), 537 – 546.

Part 3: Full paper analysis Excluded: Abstract provided only: Google Scholar 1. Ávila-Gálves, M. Á., Espín, J. C and González-Sarrías, A., 2018. Physiological Relevance of the Antiproliferative and Estrogenic Effects of Dietary Polyphenol Aglycones versus Their Phase-II Metabolites on Breast Cancer Cells: A Call of Caution. Journal of Agriculture and Food Chemistry [online], 66 (32), 8547 – 8555.

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Liver cancer inclusion and exclusion Genetics Part 1: Title screening Inclusion NCBI 1. Dluzen, D. F., Sutliff, A. K., Chen, G., et al., 2016. Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines. Journal of Pharmacology and Experimental Therapeutics [online], 359 (1), 182 – 193. 2. De Mattia, E., Cecchin, E., Polesel, J., et al., 2017. UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk in Caucasian population. Liver International [online], 37 (9), 1345 – 1353. 3. Balliet, R. M., Chen, G., Dellinger, R. W and Lazarus, P., 2010. UDP- glucuronosyltransferase 1A10: activity against the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a potential role for a novel UGT1A10 promoter deletion polymorphism in cancer susceptibility. Drug Metabolism and Disposition [online], 38 (3), 484 – 490.

Google scholar 1. Wang, L. Z., Ramírez, J., Yeo, W., et al., 2013. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS ONE [online], 8 (1), e54522. 2. Borel, F., Han, R., Visser, A., et al., 2012. Adenosine triphosphate- binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs Hepatology [online], 55 (3), 821 - 832. 3. Zhao, J., Yu, B-Y., Wang, D-Y., et al., 2010. Promoter polymorphism of MRP1 associated with reduced survival in hepatocellular carcinoma. World Journal of Gastroenterology [online], 16 (48), 6104 – 6110. 4. Yang, Z., Zhou, L., Wu, L. M., et al., 2010. Combination of polymorphisms within the HDAC1 and HDAC3 gene predict tumor recurrence in hepatocellular carcinoma patients that have undergone

261

transplant therapy. Clinical Chemistry and Laboratory Medicine [online], 48 (12), 1785 – 1791.

Exclusion Duplicates NCBI 1. Sun, D., Jones, N. R., Manni, A., et al., 2013. Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prevention Research [online], 6 (7), 719 – 730. 2. Girard, H., Thibaudeau, J., Court, M. H., et al., 2005. UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver. Hepatology [online], 42 (2), 448 – 457. 3. Innocenti, F., Iyer, L,. Ramírez, J., et al., 2001. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metabolism and Disposition [online], 29 (5), 686 – 692. 4. Sun, D., Chen, G., Dellinger, R. W., et al., 2006. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Research [online], 8 (4), doi: 10.1186/bcr1539. 5. Vargens, D. D., Neves, R. R., Bulzico, D. A., et al., 2011. Association of the UGT1A1-53(TA)n polymorphism with L-thyroxine doses required for thyrotropin suppression in patients with differentiated thyroid cancer. Pharmacogenetics and Genomics [online], 21 (6), 341 – 343. 6. Bushey, R. T., Chen, G., Blevins-Primeau, A. S., et al., 2011. Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenetics and Genomics [online], 21 (2), 55 – 65.

Not relevant Scopus 1. Sun, D., Jones, N. R., Manni, A., et al., 2013. Characterization of raloxifene glucuronidation: Potential role of UGT1A8 genotype on

262

raloxifene metabolism in vivo. Cancer Prevention Research [online], 6 (7), 719 – 730. 2. Ino, T., Ohtani, T and Yoshimi, I., 2011. Urinary biomarkers for secondhand smoke. Journal of Clinical Laboratory Analysis [online], 25 (5), 354 – 358. 3. Bushey, R.T., Chen, G., Blevins-Primeau, A. S., et al., 2011. Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenetics and Genomics [online], 21 (2), 55 – 65. 4. Sun, D., Chen, G., Dellinger, R.W., Sharma, A. K., et al., 2010. Characterization of 17-dihydroexemestane glucuronidation: Potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenetics and Genomics [online], 20 (10), 575 – 585. 5. Darbari, D.S., Minniti, C.P., Rana, S., et al., 2008. Pharmacogenetics of morphine: Potential implications in sickle cell disease. American Journal of Hematology [online], 83 (3), 233 – 236. 6. Chen, G., Blevins-Primeau, A.S., Dellinger, R.W., et al., 2007.Glucuronidation of nicotine and cotinine by UGT2B10: Loss of function by the UGT2B10 codon 67 (Asp>Tyr) polymorphism. Cancer Research [online], 67 (19), 9024 – 9029. 7. Jinno, H., Hanioka, N., Tanaka-Kagawa, T., et al., 2005. Transfection assays with allele-specific constructs: functional analysis of UDP- glucuronosyltransferase variants. Methods in Molecular Biology [online], 311, 19 – 29. 8. Wells, P.G., Mackenzie, P. I., Chowdhury, J. R., et al., 2004. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metabolism and Disposition [online], 32 (3), 281 – 290. 9. Innocenti, F., Iyer, L., Ramírez, J., Green, M.D., et al., 2001. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metabolism and Disposition [online], 29 (5), 686 – 692. 10. Sandanaraj, E., Jada, S. R., Shu, X., et al., 2008. Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients. Pharmacogenomics Journal [online], 8 (3), 174 – 185.

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11. Sun, D., Chen, G., Dellinger, R. W., et al., 2006. Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Research [online], 8 (4), DOI: 10.1186/bcr1539. 12. Girard, H., Villeneuve, L., Court, M. H., et al., 2006. The novel UGT1A9 intronic I399 polymorphism appears as a predictor of 7-ethyl-10- hydroxycamptothecin glucuronidation levels in the liver. Drug Metabolism and Disposition [online], 34 (7), 1220 – 1228. 13. Girard, H., Thibaudeau, J., Court, M. H., et al., 2005. UGT1A1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver. Hepatology [online], 42 (2), 448 – 457. 14. Nakajima, M., Yokoi, T., 2005. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metabolism and Pharmacokinetics [online], 20 (4), 227 – 235. 15. Wells, P.G., Mackenzie, P. I., Chowdhury, J. R., Guillemette, C., Gregory, P. A., Ishii, Y., Hansen, A. J., Kessler, F. K., Kim, P. M., Chowdhury, N.R and Ritter, J.K., 2004.Glucuronidation and the UDP- glucuronosyltransferases in health and disease. Drug Metabolism and Disposition [online], 32 (3), 281 – 290. 16. Tukey, R. H and Strassburg, C. P., 2000. Human UDP- glucuronosyltransferases: Metabolism, expression, and disease. Annual Review of Pharmacology and Toxicology [online], 40, 581 – 616.

Web of Science 1. Iyer, D and Parani, M., 2018. Screening of patients with Gilbert's Syndrome from South India identifies UGT1A1*28 as the most predominant mutation in UGT1A1 gene. Research Journal of Biotechnology [online], 13 (4), 37 – 40. 2. Chen, G., Luo, S., Kozlovich, S., et al., 2016. Association between Glucuronidation Genotypes and Urinary NNAL Metabolic Phenotypes in Smokers. Cancer Epidemiology, Biomarkers & Prevention [online], 25 (7), 1175 – 1184.

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Google Scholar 1. Court, M. H., 2010. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metabolism Reviews [online], 42 (1), 209 – 224. 2. Ramírez, J., Ratain, M. J and Innocenti, F., 2010.Uridine 5´-diphospho- glucuronosyltransferase genetic polymorphisms and response to cancer chemotherapy. Future Oncology [online], 6 (4), 563 – 585. 3. Jones, N. R., Sun, D., Freeman, W. R P., et al., 2012. Quantification of Hepatic UDP glucuronosyltransferase 1A splice variant expression and correlation of UDP glucuronosyltransferase 1A1 variant expression with glucuronidation activity. Journal of Pharmacology and Experimental Therapeutics [online], 342 (3), 720 – 729. 4. Street, C. M., Zhu, Z., Finel, M., et al., 2017. Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases

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(UGTs) and influence of genetic polymorphisms. Xenobiotica [online], 47 (1), 1 – 10. 5. Fujiwara, R., Yoda, E and Tukey, R. H., 2018. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans. Drug Metabolism and Pharmacokinetics [online], 33 (1), 9 – 16. 6. Dumas, M. E., Kinross, J and Nicholson, J. K., 2014. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology [online], 146 (1), 46 – 62. 7. Inoue, K., Sonobe, M., Kawamura, Y., et al., 2013. Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. The Tohoku Journal of Experimental Medicine [online], 229 (2), 107 – 114. 8. Tojcic, J., Benoit-Biancamano, M. O., Court, M. H., et al., 2009.In vitro glucuronidation of fenofibric acid by human UDP- glucuronosyltransferases and liver microsomes. Drug Metabolism and Disposition [online], 37 (11), 2235 – 2243. 9. Kusuhara, H and Sugiyama, Y., 2009. Drug Metabolism and Pharmacokinetics [online], 24 (1), 37 – 52. 10. Bernabeu, I., Marazuela, M., Lucas, T., et al., 2010. Pegvisomant- Induced Liver Injury Is Related to the UGT1A1*28 Polymorphism of Gilbert's Syndrome. The Journal of Clinical Endocrinology and Metabolism [online], 95 (5), 2147 – 2154.

Keyword(s) not specified NCBI 1. Bellemare, J., Rouleau, M., Harvey, M., et al., 2011. Immunohistochemical expression of conjugating UGT1A-derived isoforms in normal and tumoral drug-metabolizing tissues in humans.

The Journal of Pathology [online], 223 (3), 425 – 435.

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Part 2: Abstract screening Inclusion NCBI 1. Dluzen, D. F., Sutliff, A. K., Chen, G., et al., 2016. Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines. Journal of Pharmacology and Experimental Therapeutics [online], 359 (1), 182 – 193. 2. De Mattia, E., Cecchin, E., Polesel, J., et al., 2017. UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk

in Caucasian population. Liver International [online], 37 (9), 1345 – 1353.

Google scholar 1. Wang, L. Z., Ramírez, J., Yeo, W., et al., 2013. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS ONE [online], 8 (1), e54522 Exclusion Glucuronides not reported NCBI 1. Balliet, R. M., Chen, G., Dellinger, R. W., et al., 2010. UDP- glucuronosyltransferase 1A10: activity against the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a potential role for a novel UGT1A10 promoter deletion polymorphism in cancer susceptibility. Drug Metabolism and Disposition [online], 38 (3), 484 – 490. 2. De Mattia, E., Cecchin, E., Polesel, J., et al., 2017. UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk in Caucasian population. Liver International [online], 37 (9), 1345 – 1353.

Google scholar 1. Borel, F., Han, R., Visser, A., et al., 2012. Adenosine triphosphate‐ binding cassette transporter genes up‐regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs. Hepatology [online], 55 (3), 821 – 832.

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2. Zhao, J., Yu, B-Y., Wang, D-Y and Yang, J-E., 2010. Promoter polymorphism of MRP1 associated with reduced survival in hepatocellular carcinoma. World Journal of Gastroenterology [online], 16 (48), 6104 – 6110. 3. Yang, Z., Zhou, L., Wu, L. M., et al., 2010. Combination of polymorphisms within the HDAC1 and HDAC3 gene predict tumor recurrence in hepatocellular carcinoma patients that have undergone transplant therapy. Clinical Chemistry and Laboratory Medicine [online], 48 (12), 1785 – 1791.

Part 3: Full paper analysis Exclusion Cell line studies NCBI 1. Dluzen, D. F., Sutliff, A. K., Chen, G., et al., 2016. Regulation of UGT2B Expression and Activity by miR-216b-5p in Liver Cancer Cell Lines. Journal of Pharmacology and Experimental Therapeutics [online], 359 (1), 182 – 193.

Glucuronides reported that are not associated to disease Google scholar 1. Wang, L. Z., Ramírez, J., Yeo, W., et al., 2013. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS ONE [online], 8 (1), e54522.

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Lifestyle Part 1: Title screening Inclusion Google Scholar 1. Armitage, E. G and Barbas, C., 2014. Metabolomics in cancer biomarker discovery: current trends and future perspectives. Journal of Pharmaceutical and Biomedical Analysis [online], 87, 1 – 11.

Exclusion Not relevant Google Scholar 1. Lee, M-R., Park, H., Bae, S., et al., 2014. Urinary bisphenol A concentrations are associated with abnormal liver function in the elderly: a repeated panel study. Journal of Epidemiology and Community Healthy [online], 68 (4), 312 – 317. 2. Mori, Y., Koide, A., Tatematsu, K., et al., 2005. Effects of α-naphthyl isothiocyanate and a heterocyclic amine, PhIP, on cytochrome P-450, mutagenic activation of various carcinogens and glucuronidation in rat liver. Mutagenesis [online], 20 (1), 15 – 22.

Part 2: Abstract Excluded Glucuronides not reported Google Scholar 1. Armitage, E. G and Barbas, C., 2014. Metabolomics in cancer biomarker discovery: current trends and future perspectives. Journal of Pharmaceutical and Biomedical Analysis [online], 87, 1 – 11.

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Appendix 3: Evidence of permission granted

Permission granted on Monday 15th July 2019 by Wiley for Figure 4.3 : Dear Jack,

Thank you for your email.

Permission is granted for you to use the material requested for your thesis/dissertation subject to the usual acknowledgements (author, title of material, title of book/journal, ourselves as publisher) and on the understanding that you will reapply for permission if you wish to distribute or publish your thesis/dissertation commercially.

You should also duplicate the copyright notice that appears in the Wiley publication in your use of the Material. Permission is granted solely for use in conjunction with the thesis, and the material may not be posted online separately.

Any third-party material is expressly excluded from this permission. If any material appears within the article with credit to another source, authorisation from that source must be obtained.

Should you require any further information, please do not hesitate to contact me.

Kind regards,

Paisley Chesters Permissions Co-Ordinator

275

Permission granted for Figure 1.5 by Elsevier

276

Appendix 4: Supplementary information

A4 1.0: Organic anion transporters Organic anion transporters (OATs) are 12 transmembrane (TMB) structures (Figure 4.2) which require sodium (Na+) concentration gradients for molecule transportation. OATs are expressed in the kidneys and liver, on the basolateral surface of the membrane (Masuda et al. 1997; Takeuchi et al. 2001; Shikano et al. 2004; Eraly et al. 2006; Eraly et al. 2008; Zhu et al. 2012; Preising et al. 2015; Wu et al. 2017). OATs may work in conjunction with ABC transporters in a synergistic manner for molecule transportation. Alternatively, OATs may function independently without synergistic function with ABC transporters. An example of a predicted structure of a human OAT, OAT4, has been depicted in Figure A4 1.0

Figure A4 1.0: Predicted transmembrane topological structure of human organic anion transporter 4. Structure constructed using Protter (Omasits et al. 2014). OAT4 accession number: AAK68155.1

A5 1.2 Organic anion transporter regulation OATs are subjected to regulation by PKC and ubiquitination. OAT1 for instance, is subjected ubiquitination degradation, with ten potential ubiquitination sites located between TMD2, 3, 6, 7, 8, 9 and on the C terminal (Li et al. 2013; Xu et

277 al. 2016). Degradation of OAT1 could lead to the development of certain diseases and conditions. For example, bilirubin is a substrate of OAT1, therefore OAT1 degradation could contribute to the development of jaundice.

278

Table 1: Phosphorylation sites of ABC transporters PhosphoSitePlus®: Hombeck et al. (2004), was used to confirm the phosphorylation sites of ABC transporters.

ABC Transporter Amino acid Amino acid Reference residue position Serine 1042 Threonine 1242 (Roosbeek et al. ABCA1 Threonine 1243 2002) Serine 1255 Serine 2054

Serine 1327 (Oslen et al. 2006) Serine 1331 Tyrosine 1694 (Rikova et al. 2007) ABCA2 Tyrosine 2178 (Dephoure et al. 2008) Tyrosine 2186 (Rikova et al. 2007) Threonine 2412 (Dephoure et al. 2008)

Tyrosine 1265 (Rikova et al. 2007; ABCA3 Tyrosine 1268 Cascado et al. Tyrosine 1349 2013)

ABCA4 Tyrosine 901 (Tsybovsky et al. 2011)

Tyrosine 22 (Rikova et al. 2007 ABCA5 Tyrosine 58 (Rikova et al. 2007 Tyrosine 1299 (Hornbeck et al. 2004)

ABCA6 Tyrosine 464 (Gu et al. 2011) Serine 809 (Bian et al. 2014)

ABCA7 Serine 2133 (Bian et al. 2014)

Threonine 256 (Olsen et al. 2010) ABCA8 Serine 1507 (Olsen et al. 2010) Serine 1570 (Bian et al. 2014) ABCA9 Serine 1333 (Mertins et al. 2014)

Serine 91 (Raijmakers et al. 2010) ABCA11 Threonine 112 Threonine 115 (Yu et al. 2007) Threonine 118

ABCA13 Serine 2300 (Mertins et al. 2016) Tyrosine 3866 (Palacios-Moreno et al. 2015)

279

Serine 661 (Dephoure et al. 2008) ABCB1 Serine 667 (Chambers et al. Serine 683 1994)

ABCB2 Threonine 545 (Mertins et al. 2016) Threonine 694 (Tsai et al. 2015)

ABCB3 Threonine 458 (Mertins et al. 2016)

ABCB4 Not applicable

ABCB5 Threonine 1236 (Mertins et al. 2014)

ABCB6 Serine 456 (Stuart et al. 2015)

Serine 199 (Gu et al. 2011) ABCB7 Threonine 257 (Mertins et al. 2014) Threonine 600 (Tsai et al. 2015) Serine 743 (Mertins et al. 2016)

Serine 233 (Bian et al. 2014) ABCB8 Serine 544 (Mertins et al. 2014; Mertins et al. 2016) Serine 577 (Tsai et al. 2015) ABCB9 Not applicable

ABCB10 Threonine 363 (Alcolea et al. 2012)

Serine 690 ABCB11 Serine 694 (Bian et al. 2014) Serine 704

Serine 915 (Palacios-Moreno et al. 2015) ABCC1 Serine 918 (Palacios-Moreno et al. 2015) Serine 930 (Mertins et al. 2016)

Serine 878 (Bian et al. 2014) ABCC2 Serine 930 Mertins et al. 2014 Serine 938 (Bian et al. 2014)

Serine 1153 (Zhao et al. 2011) Serine 1438 (Bian et al. 2014)

Serine 629 (Mertins et al. 2016) Threonine 646 (Mertins et al. 2016) ABCC4 Serine 655 (Mertins et al. 2016) Serine 668 (Mertins et al. 2016) Tyrosine 1259 (Tsai et al. 2015)

280

Serine 509 (Mertins et al. 2016) Serine 558 (Stuart et al. 2015) ABCC5 Tyrosine 1166 (Mortiz et al. 2010) Tyrosine 1423 (Palacios-Moreno et al. 2015)

Serine 294 (Klammer et al. 2012) ABCC6 Serine 681 (Gauci et al. 2009) Serine 902 (Yu et al. 2007) Serine 1286 (Bian et al. 2014) Serine 1310 (Gauci et al. 2009)

ABCC8 Not applicable

ABCC9 Threonine 170 (Mertins et al. 2014)

ABCC10 Threonine 463 (Cantin et al. 2008) Serine 467 (Cantin et al. 2008)

ABCD4 Threonine 116 (Mertins et al. 2016)

281

Table 2: Structural comparison of phase I cytochrome p450 substrates in relation to the associated cytochrome p450. Cytochrome Molecule structure Molecule name Reference p450 isoform

Bilirubin (Zhang et CYP1A1 al. 2005)

PhIP (Dingley et al. 1999)

Cocaine (Sanchez- Ramos 2004)

CYP1A2 Bilirubin (Zhang et al. 2005)

(Escobar- Nicotine Chávez et al. 2011)

282

Acetaminophen (Singh et al. 2018)

Methadone (Bouquié et CYP2B6 (R- and S- al. 2015) enantiomers)

(Casale et Ketamine al. 2012)

Clotrimazole (Crowley and Gallagher 2014)

Irinotecan (KEGG CYP3A4 2018)

Acetaminophen (Singh et al. 2018)

283

Methadone (Bouquié et (R- and S- al. 2015) enantiomers)

Testosterone (Almaiman 2018)

(Revathi Oestrogen and (oestradiol) Prashanth 2015)

(Hall and MDMA Henry 2006)

Ketamine (Casale et al. 2012)

Anthocyanin (Adedokun et al. 2016)

284

Hydrocortisone (EMBL-EBI 2019)

(Magnuson CYP2E1 Aspartame et al. 2007)

Ethanol (Zaki et al. 2011)

285

Table 3: Phase II conjugation enzymes and associated substrate. Phase II Molecule structure Molecule Reference for conjugation name molecule enzyme structure

UGT1A1 Bilirubin (Zhang et al. 2005)

PhIP (Dingley et al. 1999)

Irinotecan (KEGG 2018)

Ethanol (Zaki et al. 2011)

UGT1A6 Bilirubin (Zhang et al. 2005)

(Dingley et PhIP al. 1999)

Irinotecan (KEGG 2018)

286

Testosterone (Almaiman UGT2B15 2018)

Oestrogen (Revathi and (oestradiol) Prashanth 2015)

UGT2B17 Testosterone (Almaiman 2018)

Oestrogen (Revathi and (oestradiol) Prashanth 2015)

Nicotine (Escobar- Chávez et al. 2011)

287

Table 4: Phase III ABC transporters and molecule substrates Phase III Molecule structure Molecule Reference ABC name for transporter molecule structure

ABCA1 (Cholesterol Ethanol (Zaki et al. Efflux 2011) Regulatory Protein)

Nicotine (Escobar- Chávez et al. 2011)

ABCB1 (MDR1) Methadone (Bouquié (R- and S- et al. enantiomers) 2015)

(KEGG Irinotecan 2018)

Acetaminophen (Singh et al. 2018)

288

MDMA (Hall and Henry 2006)

Hydrocortisone (EMBL- EBI 2019)

ABCC1 (MRP1) Bilirubin (Zhang et al. 2005)

Testosterone (Almaiman 2018)

ABCC2 (MRP2) Bilirubin (Zhang et al. 2005)

289

ABCC3 (MRP3) Bilirubin (Zhang et al. 2005)

ABCC4 (MRR4) Irinotecan (KEGG 2018)

Acetaminophen (Singh et al. 2018)

Testosterone (Almaiman 2018)

ABCC12 Acetaminophen (Singh et (CFTR/MRP9) al. 2018)

ABCG2 (BCRP) Irinotecan (KEGG 2018)

290

Ketamine (Casale et al. 2012)

Oestrogen (Revathi (oestradiol) and Prashanth 2015)

PhIP (Dingley et al. 1999)

(Escobar- Nicotine Chávez et al. 2011)

291